Cardiovascular disease (CVD) is the leading cause of death for both men and women in the United States. Since cardiac myocytes have limited ability to regenerate, their malfunction or significant loss due to aging or diseases can lead to lethal consequences. Recent studies have provided exciting evidence to support the notion that stem cells may offer an enormous potential for regenerative therapy. However one intractable barrier to cell therapy in all tissues is overcoming the confounding hurdle of scars that ensue from acute and robust inflammatory responses arising during tissue injury.
CVD is the leading cause of morbidity and mortality in the US (9-12). Therapeutic strategies using cell-based therapy to combat ischemic cardiomyopathy have not produced full restorative functions (13-15). Moreover, previous studies have demonstrated that transplanted stem cells do not engraft or survive long term due to apoptosis, increased collagen deposition, ischemic environment, and increased inflammation related factors such as free radicals and cytokines in the host myocardium (16-18).
Arachidonic acid is released in response to tissue injury and can be metabolized through the cyclooxygenase (COX), lipoxygenase (LOX) and cytochrome P450 (CYP450) pathways (FIG. 1). The CYP450 epoxygenase pathway generates epoxyeicosatrienoic acids (EETs) which modulate ion transport and gene expression, producing vasorelaxation, anti-inflammatory and pro-fibrinolytic effects (19). EETs are further metabolized by soluble epoxide hydrolases (sEH) to form the corresponding dihydroxyeicosatrienoic acids (DHETs) with a significant reduction in anti-hypertensive and anti-inflammatory activities (19-21).